This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. Reproductive history has a significant impact on development of breast cancer. Nulliparity is a significant risk factor for breast cancer. Pregnancy and lactation are associated with reduced risk. Apoptotic cell death of mammary epithelium during postlactational involution may offer an explanation for these differences in risk. Apoptosis is a physiological cell death that eliminates damaged, excess, or potentially deleterious cells while maintaining overall tissue integrity. [In the course of mammary gland involution, the bulk of secretory epithelium undergoes apoptosis.] Thus, during mammary involution many of the cells at risk for neoplastic development may be eliminated by apoptotic cell death. Consistent with this hypothesis, experimental studies of liver, B-cell and mammary neoplasias and a recent clinical study of human mammary hyperplasias suggest that failure or inhibition of apoptosis can contribute to tumorigenesis. These observations suggest that not only may a failure or misregulation of apoptosis contribute to mammary tumorigenesis but also regulation of apoptosis may play an important role in prevention of mammary neoplasia. Both of these possibilities have potential for therapeutic application. The goal of this project is to test the function of cDNAs isolated from involuting mammary epithelium in order to identify genes that regulate and execute apoptosis and to evaluate their potential contribution to cell death in mammary epithelial cells. This goal will be accomplished by: 1) [DNA sequence, Northern blot, immunoblot and immunohistochemical analyses to characterize genes corresponding to clones 4 and 121, cDNAs which are differentially expressed in involuting mammary glands], 2) [expressing genes implicated in the control or execution of cell death in cell lines derived from normal mammary gland, mammary hyperplasias and tumors to test their function] and 3) utilizing a two-hybrid yeast system to identify proteins that interact with the protein products of genes suspected of regulating or executing post-lactational apoptotic cell death].